ArticleProceedings of the National Academy of Sciences of the United States of America2015
Modulation of folding energy landscape by charge-charge interactions: linking experiments with computational modeling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- How a highly acidic SH3 domain folds in the absence of its charged peptide target.Protein science : a publication of the Protein Society · 2023Article
- Coarse-Grained Simulations of Protein Folding: Bridging Theory and Experiments.Methods in molecular biology (Clifton, N.J.) · 2022Article
- The Role of Electrostatics and Folding Kinetics on the Thermostability of Homologous Cold Shock Proteins.Journal of chemical information and modeling · 2020Article
- Networks of electrostatic and hydrophobic interactions modulate the complex folding free energy surface of a designed βα protein.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- The protonation state of an evolutionarily conserved histidine modulates domainswapping stability of FoxP1.Scientific reports · 2019Article
- Electrostatic control of calcineurin's intrinsically-disordered regulatory domain binding to calmodulin.Biochimica et biophysica acta. General subjects · 2018Article
- Electrostatic Interactions in Protein Structure, Folding, Binding, and Condensation.Chemical reviews · 2018Review
- Effects of pH and Salt Concentration on Stability of a Protein G Variant Using Coarse-Grained Models.Biophysical journal · 2018Article
- Charge Shielding Prevents Aggregation of Supercharged GFP Variants at High Protein Concentration.Molecular pharmaceutics · 2017Article
- Computational tools help improve protein stability but with a solubility tradeoff.The Journal of biological chemistry · 2017Article
- Electrostatic effects on the folding stability of FKBP12.Protein engineering, design & selection : PEDS · 2016Article
- Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell.Chemical reviews · 2016Review
- Using Kinetic Network Models To Probe Non-Native Salt-Bridge Effects on α-Helix Folding.The journal of physical chemistry. B · 2016Article
- Electrostatics, structure prediction, and the energy landscapes for protein folding and binding.Protein science : a publication of the Protein Society · 2016Article
- Protein stability: computation, sequence statistics, and new experimental methods.Current opinion in structural biology · 2015Review
- Native contact density and nonnative hydrophobic effects in the folding of bacterial immunity proteins.PLoS computational biology · 2015Article
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Authors and funding
3 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The kinetics of folding-unfolding of a structurally diverse set of four proteins optimized for thermodynamic stability by rational redesign of surface charge-charge interactions is characterized experimentally. The folding rates are faster for designed variants compared with their wild-type proteins, whereas the unfolding rates are largely unaffected. A simple structure-based computational model, which incorporates the Debye-Hückel formalism for the electrostatics, was used and found to qualitatively recapitulate the experimental results. Analysis of the energy landscapes of the designed versus wild-type proteins indicates the differences in refolding rates may be correlated with the degree of frustration of their respective energy landscapes. Our simulations indicate that naturally occurring wild-type proteins have frustrated folding landscapes due to the surface electrostatics. Optimization of the surface electrostatics seems to remove some of that frustration, leading to enhanced formation of native-like contacts in the transition-state ensembles (TSE) and providing a less frustrated energy landscape between the unfolded and TS ensembles. Macroscopically, this results in faster folding rates. Furthermore, analyses of pairwise distances and radii of gyration suggest that the less frustrated energy landscapes for optimized variants are a result of more compact unfolded and TS ensembles. These findings from our modeling demonstrates that this simple model may be used to: (i) gain a detailed understanding of charge-charge interactions and their effects on modulating the energy landscape of protein folding and (ii) qualitatively predict the kinetic behavior of protein surface electrostatic interactions.
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